Conversing with Professor Antoine Italiano, a worldwide expert on early drug development, phase I oncology trials and immuno-oncology, upon the release of a recent article in Clinical Cancer Research.

Professor Italiano delves into the major insights from this groundbreaking publication and offers his perspective on the upcoming trajectory of cancer immunotherapy.

Read the paper here, titled “Upregulation of Indoleamine 2,3-dioxygenase 1 in tumor cells and tertiary lymphoid structures is a hallmark of inflamed non-small cell lung cancer”.

 

Pr. Italiano: The key to identifying biomarkers for immunotherapy lies in patient samples. I am very indebted to the generosity of the patients who consented to participate in the Bergonié Institute Profiling program.

 

What are the current challenges of immunotherapy for lung cancer management?

Pr. Italiano: Lung cancer ranks as the top cause of cancer-related deaths in Western countries. Until recently, its primary treatment was chemotherapy, which had limited efficacy with response rates under 20%.

Subsequent advances introduced immunotherapy, specifically using monoclonal antibodies that target the programmed cell death-1 (PD-1) or its ligand (PD-L1). However, this approach has been effective in fewer than 30% of patients.

The primary challenge now lies in expanding the percentage of lung cancer patients who can benefit from immunotherapy. This requires a deeper understanding of resistance mechanisms and the development of strategies to overcome them.


Why are tertiary lymphoid structures the backdrop of this research?

Pr. Italiano: For several years, my team has been investigating the role of B cells in a cancer’s response to immunotherapy. These cells are primary components of tertiary lymphoid structures (TLS) found in inflamed tissues.

Our research has demonstrated that the presence of TLS enhances the likelihood of a positive response to immune checkpoint inhibitors across various cancer types. However, this finding is not universally applicable, as not all patients with TLS-positive tumors exhibit a response to the treatment.

What key results did you prove?

Pr. Italiano: This research seeks to elucidate why certain lung cancer patients with TLS exhibit resistance to immunotherapy (PD-1/PD-L1).

To achieve this, we delved into specific facets of tumor metabolism, emphasizing the kynurenine pathway’s immunosuppressive function. Our primary focus was the indoleamine 2,3-dioxygenase (IDO) enzyme, pivotal in the conversion of tryptophan to kynurenine. Our findings indicate a strong correlation between IDO activity and a favorable treatment response in these patients.

Notably, and this underscores the novelty of our study, we propose that IDO acts to modulate TLS activity in these scenarios.


What are the clinical implications of these findings?

Pr. Italiano: A direct implication of our findings suggests the combination of commonly utilized checkpoint inhibitors with an IDO inhibitor, specifically targeting the identified subgroup of lung cancer patients with an inflamed tumor microenvironment. This approach signifies a significant stride towards precision medicine in cancer immunotherapy.

Furthermore, with the right patient selection, IDO inhibitors could see a resurgence in interest, underscoring the potential of this therapeutic strategy.

To finish, what immunotherapy will be like in the future?

Pr. Italiano: The future of immunotherapy strategies hinges on precise patient selection to enhance efficacy.

Given that knowledge in immuno-oncology is doubling approximately every two years, integrative approaches that consolidate diverse research findings will undoubtedly enrich cancer immunotherapy.

For each patient, we should have access to an optimal combination of treatments guided by a specific array of biomarkers. I am confident that this will be realized through the power of artificial intelligence!

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